Malignancy rates for Bethesda III and IV thyroid nodules ... tients presenting thyroid nodules with

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    Malignancy rates for Bethesda III and IV thyroid nodules: a retrospective study of the correlation between fine-needle aspiration cytology and histopathology Busra Yaprak Bayrak* and Ahmet Tugrul Eruyar


    Background: Fine-needle aspiration cytology (FNAC) has become a well-established modality in the diagnosis, staging and follow-up of thyroid nodules. FNAC outcomes are routinely classified using the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), facilitating appropriate clinical management. Bethesda categories III and IV encompass varying risks of malignancy. This retrospective study established a possible association between these cytological categories and malignancy rates in patients treated at a single institution.

    Methods: Over a 6-year period, 11,627 FNAC procedures were performed on thyroid nodules. Of these, 814 (59.63%) patients were submitted to thyroidectomy. The nodules of 108 patients were classified as Bethesda category III and 47 patients as Bethesda category IV. Patient data were reviewed to establish a correlation between the FNAC results and the final histopathological analyses.

    Results: The rates of malignancy among patients who underwent surgery were 25% for category III and 27.6% for category IV, with no significant differences between categories (p = 0.67). The pathological parameters of malignant nodules, namely tumour type, size, encapsulation, invasion into the thyroid capsule, extrathyroidal extension and lymphovascular invasion did not significantly differ between the groups (p > 0.05).

    Conclusions: This paper provides a more precise correlation of malignancy rates with thyroid nodules classified as Bethesda categories III and IV, as our findings are comparable to the literature, giving malignancy rates ranging from 10 to 30% for category III and 25–40% for category IV. Use of the BSRTC is heterogeneous across institutions, and there is some degree of subjectivity in the distinction between categories III and IV; therefore, it is crucial to estimate the rates of malignancy at each institution. Molecular assays are of increasing importance in determining the need for surgical intervention for thyroid lesions. Gene expression assays using FNAC material may demonstrate a high predictive value for cytologically indeterminate thyroid nodules diagnosed as Bethesda classes III and IV.

    Keywords: Fine-needle aspiration cytology, Thyroid nodule, Thyroidectomy, Malignancy rate

    © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

    * Correspondence: Department of Pathology, Faculty of Medicine, Kocaeli University, 41380 Kocaeli, Turkey

    Yaprak Bayrak and Eruyar BMC Endocrine Disorders (2020) 20:48

  • Background Fine-needle aspiration cytology (FNAC) has become a well-established diagnostic technique. It accelerates the assessment of cellular morphologic features of thyroid nodules from which the malignant risk can be deter- mined. This information is important when planning the therapeutic management of nodules, deciding in follow- up of the nodule size, repeating the biopsy or performing a total or partial thyroidectomy [1, 2]. Although FNAC is widely used in clinical diagnosis, cytologically indeter- minate thyroid nodules continue to present a diagnostic challenge for pathologists. This makes reaching a defini- tive histologic diagnosis difficult in a large number (10– 30%) of patients undergoing thyroidectomy [3]. Since 2009, The Bethesda System for Reporting Thy-

    roid Cytopathology has been used to classify FNAC find- ings based on the risk of malignancy [4, 5]. There are six cytological diagnostic categories, each with different sug- gested treatment approaches. Bethesda categories II, V and VI are well established, and therefore not subject to any disagreement in terms of their malignancy rates [6]. However, there are controversial data about the risk of malignancies, recurrence and clinical management of nodules in Bethesda categories III and IV, as the re- ported risks of malignancy vary significantly, from 10 to 30% to 25–40% (including noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP]), respectively [4]. This also leads to different approaches to choosing the best therapies. Bethesda category III de- scribes the cytological findings as “atypia of undeter- mined significance” (AUS) and “follicular lesion of undetermined significance” (FLUS), while Bethesda cat- egory IV represents “follicular neoplasm/suspicious for follicular neoplasm” (FN/SFN) [1, 4–6]. The FN/SFN category presents the greatest uncertainty, as follicular carcinomas resemble benign follicular neoplasms at the individual cellular level, hence limiting the ability of pathologist to accurately diagnose these nodules unless the tissue demonstrates any vascular or capsular inva- sion [7]. The other known cytological category of AUS/ FLUS covers a subset of lesions that are not easily classi- fied as benign, suspicious or malignant [4]. A crucial ad- vantage of the Bethesda III category is that FNAC specimens may need to be reevaluated, and in the case of a suspected follicular carcinoma, rebiopsy and opera- tive intervention should be considered [4]. The difficulty in defining the exact diagnosis of thyroid

    nodules is underlined by the fact that the probability of malignancy in AUS/FLUS or FNAC specimens remains unclear [4, 8, 9]. Some malignancy criteria such as thy- roidal or tumoral capsular and/or lymphovascular inva- sion are determinative when establishing a cancer diagnosis, which represents a significant limitation of the FNAC method. Considering these limitations and

    debates on the management of Bethesda III and IV thy- roid nodules, together with the diverse malignancy rates reported in the literature, the present retrospective study aimed to attribute an accurate malignancy rate for pa- tients with nodules classified as Bethesda III or IV. We also aimed to establish whether there is an association between these cytological categories and malignancy rates in patients, based on data collected over 6 years at a single institution.

    Methods Patients From January 2012 to July 2017, 11,627 FNAC proce- dures were performed for thyroid nodules. A total of 814 (59.63%) of these patients underwent thyroidectomy. The age of patients at the time of operation ranged from 18 to 86 years. The gender distribution showed a female preponderance, with 664 females and 150 males. The se- lection criteria for the study were patients with thyroid nodules who underwent FNAC as the primary diagnostic modality followed by total or partial thyroidectomy. After clinical and radiological diagnosis, the FNA pro- cedure was performed under ultrasound guidance. Pa- tients presenting thyroid nodules with a cytological analysis suggestive of Bethesda classes I, II, V and VI were excluded from the evaluation, along with those di- agnosed with Bethesda III and IV with no follow-up data.

    Cytology The cytopathological reports were issued by a path- ologist, following the Bethesda classification according to the literature [1, 4]. In our thyroid FNAC practice, the Bethesda III category was divided into AUS and FLUS. AUS was defined as cases with follicular cells that were mostly benign in appearance with rare nu- clear atypia, while FLUS was defined as cases with ex- tensive Hurthle cells with moderate cellularity, scant colloid with no apparent increase in lymphoid cells, and follicular epithelial cell clusters showing a micro- follicular pattern in the focal area. Aspirations were performed according to the literature [8]. Smears were either air-dried and stained with May-Grünwald- Giemsa stain without fixation, or fixed with alcohol then stained with Papanicolaou stain. The medical records of each patient were reviewed

    to establish an association between the FNAC results and the final histopathological diagnosis. The exact position of the nodule in the gland, the final histo- pathological analysis of the target nodule and other pathologic findings were considered to confirm that the cytology and histopathology results were for the same nodule.

    Yaprak Bayrak and Eruyar BMC Endocrine Disorders (2020) 20:48 Page 2 of 9

  • Histology All thyroid tissues were fixed in 10% neutralised formal- dehyde. Nodules suspected for malignity were totally embedded in paraffin, and stained with haematoxyli